The bloodstream contains numerous species of lipids circulating on lipoproteins, albumin and other lipid-binding proteins. The diversity of lipids in blood is complex, with the majority of species belonging to the phospholipids, fatty acids, and sphingolipid classes. Many members of these classes have structural roles, such as phosphatidylcholines and signaling roles, such as sphingosine-1-phosphate. One lipid species of which relatively little is known about their functions in blood are the lysophosphatidylcholines (LPCs). LPCs are structurally composed of three major lipid components: a glycerol, phosphocholine, and a fatty acid esterified to either the sn-1 or sn-2 hydroxyls of glycerol. Within cellular membranes, the majority of LPCs are synthesized through the hydrolysis of the fatty acid moiety in the sn-2 position of phosphatidylcholine lipids via phospholipase A2 enzymes. The newly generated LPCs are precursors for the re-synthesis of phosphatidylcholines through acylation reactions via lysophosphatidylcholine acyltransferase (LPCAT) enzymes that constitute the Lands Cycle of phospholipid remodeling. The Lands Cycle has been proposed to be important for regulating membrane properties, such as maintaining high levels of saturated fatty acids in phospholipids in the nuclear envelop. In addition, the Lands Cycle might also serves to keep LPCs, which are toxic to cells, at extremely low levels within cellular membranes. Interestingly, the levels of LPCs in blood are quite high, reaching about 100 μM in human and rodents (Croset, M., Brossard, N., Polette, A. & Lagarde, M. Characterization of plasma unsaturated lysophosphatidylcholines in human and rat. The Biochemical Journal 345 Pt 1, 61-67 (2000); Quehenberger, O. et al. Lipidomics reveals a remarkable diversity of lipids in human plasma. Journal of lipid research 51, 3299-3305, doi:10.1194/jlr.M009449 (2010)). A minor amount of the total blood LPCs are generated on lipoproteins in circulation by the action of lecithin-cholesterol acyltransferase on high density lipoproteins and through lipoprotein-associated phospholipase A2 on low density lipoproteins. The majority of LPCs in human and rodent blood are synthesized through the action of phospholipase A2 in the liver, where they are secreted on albumin. The most abundant of blood LPCs in human and rodents are LPC-palmitate, -stearate, and -oleate. The other classes of non-membrane localized lyso-lipids, such as lyso-PE, lyso-PI, and lyso-PS are found at extremely low levels in blood and primarily circulate on lipoproteins. The physiological function of blood LPCs has remained enigmatic, but some reports suggest a largely signaling role in inflammation, angiogenesis, cell proliferation and migration. Provided herein are new uses for LPCs in diverse areas including nutrition.
With respect to nutrition, the majority of low birth weight and extremely low birth weight preterm newborns remain in the neonatal intensive care unit (NICU) for a period equivalent to the third trimester. During this time, preterm infants that are unable to obtain adequate nutrition via the GI tract require parenteral nutritional (PN) support. Poor nutrition in preterm infants has been shown to have major negative outcomes later in life on physical and intellectual development, and increased risk for cardiovascular and metabolic disorder (Isaacs E B, et al. (2008) The effect of early human diet on caudate volumes and IQ. Pediatric research 63(3):308-314; Lapillonne A & Griffin I J (2013) Feeding preterm infants today for later metabolic and cardiovascular outcomes. The Journal of pediatrics 162(3 Suppl):S7-16.).
Although international guidelines on pediatric PN have recently been refined and have become the standard of care worldwide (Nutritional needs of the preterm infant: scientific basis and practical guidelines. Cincinnati: Digital Educational Publishing Inc., OH.; Koletzko B, Goulet O, Hunt J, Krohn K, & Shamir R (2005) 1. Guidelines on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), Supported by the European Society of Paediatric Research (ESPR). Journal of pediatric gastroenterology and nutrition 41 Suppl 2:S1-87), it is becoming widely accepted that nutritional intake in preterm infants using PN in NICUs is inadequate (Martin C R, et al. (2009) Nutritional practices and growth velocity in the first month of life in extremely premature infants. Pediatrics 124(2):649-657; Olsen I E, Richardson D K, Schmid C H, Ausman L M, & Dwyer J T (2002) Intersite differences in weight growth velocity of extremely premature infants. Pediatrics 110(6):1125-1132). Importantly, the optimal composition of nutrients in PN remains unknown (Beardsall K, et al. (2008) Early insulin therapy in very-low-birth-weight infants. The New England journal of medicine 359(18):1873-1884; Clark R H, Chace D H, & Spitzer A R (2007) Effects of two different doses of amino acid supplementation on growth and blood amino acid levels in premature neonates admitted to the neonatal intensive care unit: a randomized, controlled trial. Pediatrics 120(6):1286-1296). The standard of care is a formulation of amino acids, glucose, and lipids. The lipids are typically derived from soybean oil (up to 20%) and, in some newer formulations, contain omega-3 oils (e.g. SUMFLipid, from F). Soybean oil provides fatty acids for energy and the omega-3 and omega-6 fatty acid precursors are synthesized into docosahexaenoic acid (DHA) and arachidonic acid (ARA), which are essential for brain development. Conversion of precursor fatty acids into DHA and ARA rely on the newborn liver, which often has poor function and cannot provide adequate amounts of these essential fatty acids. Provided herein are solutions to these and other nutritional problems.
Furthermore, the role of mutations in the Mfsd2a protein as the basis of neurological diseases and deficits has also been elucidated. Disclosed herein are solutions to these medical challenges as well.